Research in the Marker laboratory is focused on understanding the biology of the prostate gland at the molecular level. Interest in understanding the biology of the prostate is driven both by the fascinating nature of the developmental processes that function during organogenesis of the prostate and by the high incidence in humans of prostatic diseases including prostatic adenocarcinoma and benign prostatic hyperplasia. The Marker lab is particularly interested in the role of intercellular communication between epithelial and mesenchymal/stromal cells during prostatic branching morphogenesis and during the progression of human prostate diseases.
One current project in the lab seeks to investigate the molecular basis of benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS). BPH is a highly prevalent condition in aging men that is frequently associated with LUTS. While the etiology of BPH and LUTS remain largely unclear, available data are consistent with the hypothesis that changing hormone levels in aging men and/or the reactivation of developmental growth-regulatory pathways are underlying causes of BPH and associated LUTS. In support of the potential role of steroid hormones in BPH and LUTS, our studies have shown that male mice treated with testosterone + estradiol (T+E2) at doses that mimic the hormonal milieu in aging human males developed benign enlargement of the prostate that was associated with the appearance of proliferating foci along the urethra that resembled developmental prostatic buds, changes in the morphology of the prostatic peri-urethral region, and a high incidence of urinary retention. The hormone-induced mouse model also exhibited gene expression changes in the prostate that have been reported to occur in human BPH including the up-regulation of Secreted frizzled related protein 1 (Sfrp1). Ongoing studies are investigating the roles of this and other developmental signaling pathways in BPH and LUTS.
A second project in the lab utilizes a forward genetic screen in mice to identify new genes involved in prostate cancer progression using transposon-mediated insertional mutagenesis. A secondary screen is used to validate the importance of candidate genes identified using the mouse model by examining the human orthologues of the candidates for altered expression in human prostate cancers. This project has already identified new candidate oncogenes, including PDE4D, that are over-expressed in human prostate cancers. Ongoing studies include continued screens for novel prostate cancer genes, functional evaluation of candidate genes to determine their roles in prostate cancer initiation and/or progression, and the investigation of new candidate cancer genes as potential targets for drug therapies.